TW200904415A - Improved bioavailability of antibiotics - Google Patents

Abstract

The object of the invention consists on the preparation of pharmaceutical formulations containing rifaximin in the shape of microgranules made gastroresistant by an insoluble polymer at pH values between 1.5 and 4.0 and soluble at pH values between 5.0 and 7.5, having the characteristic to be a higher bioavailability in comparison to other formulations, by their preparation and by their use in the manufacture of medicinal preparations useful in the treatment of inflammatory bowel diseases (IBD) and mainly Crohn's disease.

Description

200904415 IX. Description of the invention: [Technical field to which the invention belongs] The object of the present invention is composed of a pharmaceutical formulation containing rifaximin in the form of microparticles, which are collectively included in the value聚.5 and 4.0 polyδ substances which are insoluble in pH and soluble between pH 5.0 and 7.5 and have gastric resistance (gastr〇resistant); preparation thereof; /, used in the treatment of intestinal infections and inflammation Sexual enteric disease: The use of a pharmaceutical preparation such as Crohn's disease, which has improved biologic properties compared to an uncoated preparation. Dry [Prior Art]: The organ is subject to many inflammatory diseases commonly referred to as inflammatory bowel diseases, and e 'Clone' disease is a serious chronic inflammation of the infection from the oral cavity to the anal fistula. Sexual disease::: The last part (ileum, colon or both) and sometimes also observed in the colonic anal area. In the relevant part of the intestines, 'the whole pain, but the uninfected woven:= Sexual ulceration and now different symptoms such as the following: The diarrhea, abdominal pain, weight loss of the father for the rectum Surrounded by a fistula. Two-thirds of s, + ^ rhagade, or at some point in the patient's life: need three: abscesses with Crohn's disease, or complications of bleeding. °Treatment such as % Dao Yin obstruction, perforation, 3] 2XP / invention instructions (supplement) / 96-腑61277] 2 6 200904415 Intestinal flora plays a role in the intestinal inflammatory diseases and especially the cause of Crohn's disease The role is confirmed by, for example, the frequency concentrated in areas of high bacterial concentration, see Jann〇witz, HD, Inflamm

Dis., 1 998, 4 students, 29-39; can reduce the damage of re-endoscopic examination when the canal isation is detected by the deviation of fecal flow, see Rutgeerts, P., Lancet, 1991, 338 , 77 774 ; experimental models (for example, regarding the IL_1Q gene or other knock-out mice) show that spontaneous colitis is not developed if "sterile" conditions are maintained, see Blumberg R s.,

Immunol., 1 999' 11(6) '648_56; develops intestinal mucosal inflammation after contact with feces, see Harper p. η., Gut, 1985, π, 279-84; composed of ileocecal anastomosis 'Antibiotic treatment in the "cure" therapy can delay the development of both endoscopy and clinical recurrence, see Cameron JL, Ann. Surg, 992, 215 546 52 and the presence of a treatment tube or abscess sac (4) Disease (4) tribute to the sputum ν, the previous line of Crohn's disease, the use of drugs that can reduce or control inflammation, f / column such as 'cortisone ((3) rtisQnes), salicyl azo hydrazine mouth bite than bite

: 2 Zopirine), mesalazine immunosuppressive agents, chemotherapeutic agents, antibiotics and tumor necrosis factor (W)

Necrosis Factor, TNF), you can talk about it, 枓, 音, 广, protein shell inhibitor. During the acute phase of inflammatory disease, sputum, and wave, it is usually necessary to have a stronger treatment to ensure the use of parenteral confession, so that the bowel rests and is good for collapse. The healing of the tile/shellfish. The purpose of treatment is to reduce 312XP / invention manual (supplement) / 96-] 〇 / 961277〗 2 7 200904415 The frequency of low symptom reproduction and reduce the serious acute events when symptoms appear. However, with current therapies, acute events account for approximately 5 〇 _ 7 (10) of the cases, but 80% of patients will relapse. Antibiotics are commonly used to reduce the growth of bacteria in the lumen; to reduce the inflammatory state that persists due to bacterial growth; to alleviate symptoms in the acute phase of the disease, such as diarrhea, intestinal pain and bloating; and to prevent and cure septic complications, for example, Abscess, fistula and toxic state. ί The most commonly used antibiotic is systemic absorption, for example, metronidazole (with against certain parasites and many anaerobic bacteria)

= sex) and ciprofl〇xacin (having activity against bacteria such as the large intestine (囷(10)) and Enterobacter aerogenes). Metronidazole is used for 10 months at a dose of 10-20 mg/kg (Sunteriand L)

Gut' 1991 32' 1071_5)' and ciprofloxacin was used at a dose of mg/day for 6 weeks (Col(10)bel)F, Am;

Gastoenteroi., 1 999, 94’674_8), at the same time Bu Ru (10)

Am. J. Gast〇enterol•' 1996, 9 328, using a combination of two antibiotics, using 1 券 券 / > 士笔兄 / 天剂1 of metronidazole and 1000 housew / day Dosage of ciprofloxacin 〗?甘甘„ LL U Week. The high systemic bioavailability of these antibiotics is the root cause of the high side effects found in long-term heart L, and negative/oral therapy. $工..._ The use of I, /, has a negative effect. The incidence of the action of 1J in the use of metronidazole is in the range of 10% to 20% depending on the dose and the period of treatment. Including Fenyi. Tutian P is called metal taste, stomach intolerance, nausea, tongue k, sore pain, dizziness, exercise 奂 ★ solid, 4 on 4 dead, 丄 _ ^ 夫 搐 twitching and neurotoxicity. 50-85% of the patients who received long-term treatment, recorded τ heart π judgment of peripheral neuropathy, which only after 312 ΧΡ / invention manual (supplement) / 96_ ί ο /% 127712 8 200904415 after treatment for several months The percentage difference that can be reused, and the second side: the side effects of the side effects described in the study of propylfloxacin are derived from the amount of gastrointestinal tract and the duration of treatment. The most common skin reaction. Therefore:: 2: Dao: Reference to long-term treatment options such as gastrointestinal disorders. Diseases (eg antibiotics are mainly used to treat inflammatory bowel disease) The disease (for example, the pharmaceutical preparation preferably has one or more of the following characteristics: absorption of the seven parts of the intestinal tract - control of the bacterial content in the intestinal lumen, and resistance to microorganisms (eg, Γ?: positive, gram negative, A wide range of aerobic and anaerobic ingredients, long-term treatment without side effects, even if there may be a need for South Heart (for example, long-term administration and / or multiple daily administration) can be easily administered Compliance. An antibiotic with several of these properties is rifaximin (H history see The Merck Index, XH version, δ 3 (4), which is characterized by resistance to terminal gram-positive and gram-negative bacteria, including aerobic And the broad-spectrum effect of anaerobic bacteria G. The bioavailability study conducted in healthy volunteers showed that less than 1% of rifaximin was absorbed when administered orally, and it was concentrated in the intestinal cavity and in the text. In the feces (additional (10), such as anecdotal _ 乂, the drug kinetic study of rifaximin after oral administration in gun volunteers, J Clin Phaimacol Res, u (2), 51-56 ' (1994 is. Confirmed in patients with chronic intestinal infections Absorption in rifaximin (see Rizzello ' Eur. J. Clin. Pharmacol. (1 998) 54, 91-93). In addition, the low absorption profile of rifaximin causes the incidence of side effects and undesired pharmacology The risk of interaction is reduced. Therefore, rifaximin 312XP/invention specification (supplement)/96-10/96127712 9 200904415 is considered to be useful in the treatment of inflammatory chronic intestinal diseases and especially Crohn's disease. The possible efficacy of serotonin in chronic inflammatory bowel disease has been confirmed, see Gionchetti, P., Dig. Dis Sci, 1 999, 44 1220 1 'The false sputum is resistant to steroid therapy or severe Rifaximin is used in patients with ulcerative colitis. Rifaximin has been described in the Italian patents Ιτ 1 154655 (198〇) and 卯.01 61534 (1 985), and the entire contents of both patents are incorporated herein by reference as "references for all purposes. Ep with 53 Revealing a method for producing rifaximin using rifamycin (ri famycirOO as a raw material)

Merck Index, XIII Edition, 8301). Guidance notes on crystallization and drying of rifaximin in Italian Patent Application No. MI2003A002144 (2003), European Patent Application No. Ep 1557421 (2003), U.S. Patent Application Serial No. 1/728, No. 9 (2003), PCT Patent Application No. WO 〇 〇〇 〇 〇 〇 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The experimental conditions described in the I, et al. patents can result in polymorphic forms of rifaximin, respectively referred to as alpha, p, oxime, delta, and epsilon. Rifaximin is approved in certain countries for the treatment of conditions whose stage is partially or completely attributed to acute and chronic infections of the gut by Gram-positive and Gram-negative bacteria, including diarrheal syndrome, altered Intestinal flora, summer diarrh〇ea events, traveller's diarrhea and enterocolitis; prevention of infection complications during gastrointestinal surgery before and after surgery; and as an adjuvant treatment for hyperammonemia. Rifaximin is currently available in children's 312XP/invention manual (supplement)/96-1〇/96127712 200904415 in doses of ι〇〇mg and 2〇〇mg of a saponin or capsule for children, or As an ointment for the treatment of local infections. This == product' especially the study of 2〇0 mg of spirulina showed that rifampicin was effective in preventing Crohn's disease after endoscopic resection. However, in the absence of a clinical trial t, the conclusion is convinced, see Rlzzello, Gut., 2〇〇〇, 47 = Pass to A12. However, the recommended use of rifaximin (10) mg

Due to the need for up to six ingots per day for up to three months, it will be considered to be less than optimal. 2〇〇 “The profit _ is used for a dose of 600 mg/day for 16 weeks = sick, as the price is L, Am. J. GastnDenter^', = = (suppl.) S-25G. , 2003, 98 [Summary] = There is a need in the art for the treatment of a specific formula in the intestines. The previous formula is released and spread between U after administration. Therefore, 'When Leefu When the sun finally reaches the intestine, it is concentrated... increasing the dose. In order to maximize the therapeutic effect of rifaximin on the treatment of intestinal disease, a novel pharmaceutical formula is provided here, including, for example, coating only in the intestine. Dissolving the release of antibiotics against the stomach (4) membrane: 曰明微粒. This novel formulation is partially due to the high surface area of the microparticles, and the contact between the intestinal mucus is maximized. This novel formula can also be easily south. And low-dose administration, for example, for pediatric use, this new: the use of the stomach rifaximin formula; the environment (for example, its PH value is dependent on the state of fasting or food) ι·5 to about 4 (eight) with the intestinal lumen (eg 'the pH depends on the lumen considered from 5 〇 to about?· 5) pH difference between 312XP/invention specification (supplement)/96-10/96127712 11 200904415. This novel form also utilizes the polymorphic form of rifaximin. The towel is known for many years. It is generally carried out in two steps: a 峨, ay 糸 糸 knife: granulation and coating. However, the browning of the granules: 丨: many active substances are characterized by a rather fine 1 'in the case of rifaximin' between about 50% of the particle size ^ ^ micron and 4G «. Under such conditions, it is difficult to use a white bed like a fluid bed coating or steel plate Technology. Often occurs or: a random blend of coated and uncoated jobs is obtained. ' := It is found that (4) application of fluid bed technology to obtain enteric coated brown peony microparticles (and It is an object of the present invention) that it is surprisingly capable of wet granulation of a powder and coating of the formed microparticles with a polymer resistant to the stomach environment (generally referred to as enteric solution) on a :::::: Coating). The main inconvenience of wet granulation and microparticle coating which can be carried out in individual steps The time required to implement the entire procedure and: minimum to the standard. This result is derived from the combination of the amount of cifuximin in the rifaximin, the amount of the casing polymer, the amount of plasticizer and the appropriate (four) = process parameters. And unexpectedly, we have found that by this method, we have obtained antibiotics with higher bioavailability characteristics than the different uncoated formulations. This technique provides a complete coating around rifaximin. The efficiency was confirmed by SEM microscopy, as described in Figure la (scanning electron micrograph of rifaximin-resistant gastric microparticles) and lb (scanning of rifaximin-resistant gastric microparticles - single-particles) Electron micrograph), which clearly shows rifaximin 312XP / invention specification (supplement) / 96-10/96127712 12 200904415 completely coated with the casing polymer. The particle size is fairly uniform without the fine powder. If there is such an aspect - or both, it will have a negative impact on further pharmaceutical preparations. Q e can be used as a confirmation of the integrity of the coating. The rifaximin's gastric micro-dissolution distribution shows rifaxi It is completely retained at low pH and released above pH, as depicted in Figure 2 (dissolution profile). · In order to maximize the release of the active ingredient near the intestinal mucosa, the stomach environment (the pH value is self-working 5 to 4 depending on the state of fasting or food presence. PH difference. For this purpose, use has a a coating polymer material at a pH of 75, comprising: a methyl propyl (tetra) copolymer having acrylic acid or methacryl oxime, such as propylene (tetra) methacrylate copolymer (1:1) and methyl Methyl propyl acrylate methyl methacrylate copolymer (12), ς 酸 酸 酸 酸 酸 酸 ' acetic acid (four) propyl cellulose and acetic acid phthalic acid fiber =, commercially available products such as registered trademark K0LLIC0AT8, EUDRAGIT ® > AQUATERIC® > AQ0AT® 等^ is applied to the rifaximin powder or granules using a conventional device using the right tender body bed coating technique. It is dissolved by the spray (4) The film coating in medium or suspended in water is applied to the powder or granules in which the fluid bed is kept in suspension by the gas. The most commonly used organic solvent; Taiwan: 'chloroform, methanol, propanol, The triethyl g acetate and the B=, or ♦ δ-resistant lunar material can be suspended in water for application. This technique: it does not require the use of solvents and thus avoids poisons and safety-related problems. 127712 512»/Invention Manual (Supplement)_(4) 13 200904415 Can be combined with hydrated materials to add other anti-agglomerating properties Excipients, such as talc; excipients with plasticizing properties, such as glycerin, glycerol, propanol, and polyethylene glycol; surfactants, such as polysorbitol Oleic acid and polyoxyethylene ethyl ester; defoamer and anti-adhesive agent. 2 Successful application of the above technology (4) rifaximin # is very noteworthy because it is not directly spraying the casing polymer On the active ingredient, without any of the latest fluid bed technologies like granulation or the initial treatment of the active ingredient on inert particles. In fact, if there is no powder 刖 treatment, several defects will occur, such as Forming large agglomerates, granules, straight-kneading, large-scale, uneven micro-particle composition, uneven coating, rifaximin often occurs - some of these defects, the powder is composed of fine particles Extremely sparse It is electrostatically charged, hygroscopic and difficult to mix with the usual excipients in the powder. In addition, it has a tendency to separate and fail to form a homogenous mixture. In the presence of such disadvantages (4)*, the coated rifaximin needs When more than the steps and a large number of excipients are used, the human concentration will be limited. - A further advantage of the present invention is the direct use of gastric resistant microparticles of rifaximin prepared according to the techniques described herein. Capsules, or their combination with excipients and sweetness enhancers, make it possible to obtain an aqueous suspension. vs = this and more notably the 'living-resistant microparticles of rifaximin can also be directly condensed The technique is directly used for tablet preparation by adding a conventional vehicle or carrier. Another advantage is that the tablet can be divided to adjust the dosage concentration or to break it to facilitate the administration without losing the microparticles. 312XP/Invention Manual (Supplement)/96-10/96127712 14 200904415 All such opportunities are given to the preparation of rifaximin as described in the present invention

The technically important value of gastric-resistant microparticles makes them suitable for a wide range of dosages and pharmaceutical forms. In summary, the present invention exhibits a significant improvement outlined below with respect to other commercially available rifaximin formulations: the possibility of making sulphate microparticles of rifaximin in only one step, the microparticles in the stomach ( For example, a pH in the range between about 5 and about 4.0 remains insoluble and soluble in the intestine (eg, at a higher pH, such as between about 5.5 and about 75) to administer: High (four) 'allows the active ingredient to have maximum release in the intestine and (iv) maximizes contact with the intestinal mucosa due to the surface area of the micro-particles. [Embodiment] The object of the present invention consists of containing a solution which is insoluble in a pH range between 5 and 4.0 and soluble in a range of values between 5. 〇 and 75. Pharmaceutical formula of rifaximin microparticles of a curative polymer; preparation thereof; and its use in intestinal inflammatory bowel diseases, and especially in Crohn's disease. The diameter of the microparticles may range from about "open meters to about 9 microns, or more preferably between about 10 microns and about 5 microns. The pH can range from about i to about 4 9 to about 4.2, or about between about L5 and about 4, and the polymer can also be used in the pH range of about 5. Further, 7.5, or 5.0 is dissolved between about 7.7 and above. ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The solution is 312XP/invention specification (supplement)/96·10/96127712 15 200904415, and can be used as a gastric-resistant, enteric coating which releases the drug in the intestine when needed. Examples of suitable polymeric materials include, for example, acrylic polymers, methacrylic acid copolymers having acrylic acid or mercapto acrylate (for example, methacrylic acid ethyl acrylate copolymer (1:1) and methacrylic acid methacrylic acid) An oxime ester copolymer (1: 2), polyvinyl acetate phthalate, hydroxypropyl cellulose acetate and cellulose acetate phthalate, and cellulose acetate phthalate, decanoic acid via propyl fluorenyl cellulose, Polyacetate bismuth sulphate. Commercially available products include, for example, K0LLIK0AT®, EDRAGIT® (eg, EUDRAGIT (40), AQUATERIC®, AQ0AT®. Casing materials that can be dissolved at higher pH values are often used in colon-specific delivery systems, and It can be used in the gastric resistant rifaximin formulations described herein. The casing polymers used can also be modified by mixing with other non-pH sensitive coated products. Examples include, for example, a small portion of gasified tridecylamine ethyl methacrylate neutral y methacrylate sold under the trade names EUDRAGIT® and EUDRAGIT® RL; under the trade names EUDRAGIT® NE30D and EUDRAGIT® NE30 , EUDRAGIT® 40 sells neutral ester dispersions without any functional groups; polysaccharides such as amylose, polyglucamine, chondroitin sulfate, polydextrose, guar gum, inulin and fruit Glue; and other pH-independent coated products. The polymer is between about 5% and about 75% by weight of the microparticles. In other embodiments, the polymer comprises about 10% and about 60% by weight of the microparticles, 20% and about 55%, about 30% to about 80%, Between 25% and about 50%. The weight percent of the polymer to the weight of the microparticles may depend, in part, on the temperature of the polymer used, polymer 312XP/invention instructions)/96-10/96127712 16 200904415 (eg , bags, pills, capsules, etc.), and the pH at which the polymer can dissolve. The gastric-resistant rifaximin microparticles may further comprise one or more of a diluent, a plasticizer, an anti-agglomerating agent, an anti-sticking agent, a slip agent, a defoaming surfactant, or a coloring matter. These and other polymers and coatings (e.g., 'protective coatings, topcoats, and films') are described below. Suitable ingredients can be incorporated into the coating formulation, such as plasticizers, including, for example, 'adipate, sebacate, benzoate, citric acid, 'isophthalate ( Is〇ebucates), phthalic acid esters, sebacates, stearic acid vinegars and glycols. Representative plasticizers include ethoxylated monoglycerides, butyl decyl butyl hydroxyacetate, dibutyl tartrate, diethyl decanoate, dinonyl decanoate, ethyl decyl ethene Glycolate, glycerol, ethylene glycol, propylene glycol, triethylene glycol glyceride, triethylene glycol glycerin, tripropinoin, diacetyl glycerol, dibutyl phthalate, acetyl glycerol Ester, polyethylene glycol, castor oil, triethyl citrate, polyhydric alcohol, acetate, triacetin, acetyl triethyl citrate, dibenzyl citrate, citric acid Hexyl ester, butyl octyl decanoate, diisononyl phthalate, butyl octyl phthalate, dioctyl sebacate, oxidized tallate, 1,2,4- Triisooctyl phthalate, diethylhexyl phthalate, di-n-octyl phthalate, di-1-octyl phthalate, di-1-decyl phthalate, di-n-decyl citrate Ester, di-n-tridecyl phthalate, tris-2-ethylhexyl 1,2,4-benzenetridecanoate, di-2-ethylhexyl adipate, di-2-sebacate Ethylhexyl ester, di-2-ethylhexyl sebacate, dibutyl sebacate, monocaprylic glycerol Ester, and glycerol monocaprate. Other various 312XP/invention manuals (supplements)/96-10/96127712 17 200904415 layers known to those skilled in the art are also contemplated. The amount of plasticizer used in the polymeric material is typically in the range of from about 10% to about 50% by weight of the dry polymer, for example, about 10, 20, 30, 40, or 50%. The optional modifying component of the protective layer that can be applied over the enteric coating or other coating comprises a moisture permeable barrier layer (semi-permeable polymer) which can be applied sequentially after the enteric coating or other coating. To reduce the rate of moisture permeation through the enteric coating layer and thus increase the delay in drug release. Coatings generally known to those skilled in the art can be used for this purpose using a coating technique such as fluid bed coating using a solution of the polymer in water or a suitable organic solvent or via the use of an aqueous polymer dispersion. Useful materials include, for example, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and esters thereof, waxes, zein, and aqueous polymer dispersions such as EUDRAGIT® RS. And RL 30D, EUDRAGIT® NE 30D, EUDRAGIT® 40, AQUACOAT®, SURELEASE®, cellulose acetate latex. Combinations of polymers and hydrophilic polymers such as ethylcellulose, propylcellulose (KLUCEL®, Hercules Corp.), propylmethylcellulose (METHOCEL®, Dow Chemical Corp.) may also be used. , polyvinyl 吼p each biting ketone. Antifoaming agents can also be included in the gastric resistant rifaximin formulation. In one embodiment, the antifoaming agent is simethicone. 5%。 The amount of defoaming agent is typically 0% to 0.5% of the final formulation. Other reagents may be added to improve the processability of the sealant or barrier layer. Such agents include, for example, talc, colloidal vermiculite, polyvinyl alcohol, titanium dioxide, micronized vermiculite, fumed vermiculite, glyceryl monostearate, magnesium tristearate, and magnesium stearate, or mixture. 312XP/Inventive Manual (Supplement)/96-10/96127712 18 200904415 Typically, the amount of Huali et al. used to adjust the stomach resistance formula is used to obtain the substance, including the drug delivery amount and drug delivery. All of the solids of the speeding vehicle polymeric material are in the form of a plurality of particles and a plurality of particles in the formulation. It is also important to rectify the copolymer, the filler, the plasticizer, and the excipients and processing aids, from 1% by weight to about 50% by weight. Fa typically occupies the core form of the microparticles in the form of polymorphs and/or raw materials, and the shape of the lyophilized form of the coated rifaximin is selected from the above spoons. Or ε-type rifaximin. 4, β, γ, δ water; there is:: mixture of materials is homogenized by suspending the components in a demineralized two-speed mixing system (preferably U1TM homogenizer) to obtain Prepared by 15% suspension with the inter-column. A uniform suspension containing a durable material having a durability of 3 is applied and applied by a main cover or fluid bed device. ^Inventives use fluid bed technology. The mixture containing 1/spray is suspended by the outflow of warm air while being applied to the top of the apparatus (top or to the lower part (bottom spray - Wurster system))

^ and / / sexual suspension. For example, 'the fluid bed device Glatt GPG t' was used, using an 18-inch Wurster system with a K8 mm spray jet. The monthly control parameters include air inlet temperature, product overflow and film application speed 312XP/__®(_)/%_ 10/% 112 19 200904415 degrees. The film application speed and air temperature are balanced to avoid overheating of the product resulting in uneven gastric microparticle formation (products are too fast to dry) or the mixture to be coated is depolymerized to slow the drying of the product. A spray spray of between 150 and 300 g/min can be used, for example, in a 25 kg batch of gastric resistant rifaximin at the time of formulation. Spray sprays of 150 and 250 g/min can also be used, and pressures between 1 and 15 bar (1^4). Speed and pressure can be independently controlled. Maintain the temperature of the Z plant during the spray. At a constant temperature between about 20 ° C and about 4 (TC), the air temperature in the inlet can also be adjusted to be between about 4 〇t and about 75 〇, preferably between about 60 ° C and about 70. (: between. The obtained gastric microparticles are formulated for use in pharmaceutical preparations to obtain a suspension having a pleasant taste for the patient after adding water. For this purpose, the sweetener can be like a vegetable candy. , sorbitol, mannitol, saccharin, aceSulfame, neo〇hesperidin; suspensions like polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose , pectin, sanxian g gel, agar; and slip agent such as silicone added to the stomach resistant in a suitable device such as a double cone mixer or medium-to-month microparticles mixed with the aforementioned excipients can be mixed The time required to obtain the uniformity of the gastric microparticles is obtained, and the ratio of the gastric microparticles to the shaping is 1. 1 盘1盘卜1 η令普目Know that / / + + , ~ between 1.U.1 Xing 1.10, preferably at 1: 〇 5 and 1: 5 can be obtained by distributing the mixture between i gram and 300: preferably between The gastric-resistant microparticles of rifaximin obtained in a bag of rifaximin between 50 mg and _mg can be used in conjunction with 312XP/Findbacks (supplement)/96.1G/96127712 200904415 Appropriately (4) mixed directly (four) into (four) m such as candonic acid calcium, calcium sulfate, cellulose, microcrystalline cellulose u base, vitamins: corn powder, lactose, high genus, mannitol, = jiagan m # Occupation agent, such as temple powder, gelatin, sugar such as sputum, lactose, synthetic rubber, sodium oxalate, strontium methyl fiber: :: base: 雉:: poly(alkenyl), pyridone, polyethylene glycol, B Cellulose, water, each (7) agent, such as talc, magnesium stearate, calcium stearate, stearic acid:::oil: polyethylene glycol; slip agent 'such as colloidal cerium oxide, penta- such as Corn and potato starch, cross-linked carboxymethyl fiber = crospovi done, phylum powder, acetic acid: two = sweetener, such as Yan sugar, sorbitol, mannitol, saccharin , vinegar % lactone, new cellulite. Known techniques and devices known to the skilled artisan. In the =w,: \疋 double conical mixer or v-type mixer, the gastric-resistant micro-particles and the aforementioned shaping The bismuth compound required for the uniformity of the granules is obtained into the stomach-resistant micro-particles. The sputum-resistant granules are free-flowing, cohesive and lubricating, so the gastric micro-particles and excipients are resistant. Between the ratios of . . . , , 1: between 05. 05, preferably between 1··0. 15 and 1: 〇Ί: two. The obtained mixture can be pressurized with a suitable punch = ? Between milligrams and _ milligrams, preferably between i. . A dose of rifaximin between two grams of gram. The advantageous properties of the micro-particles are obtained by the use of "the above-mentioned, the sirloin is resistant to the stomach and the sputum is used to obtain a suitable blend for direct compression by adding a minimum amount of god.咖耐胃Μ2ΧΡ/Invention Manual (10) y96_1〇/%1277i2 21 200904415 The possibility of making a tablet with a blend of micro-particles presents a further point: it can maintain a proper size of 400 gram dose (good compliance) Further, the tablet may be coated with a conventional hydrophilic film to obtain a taste-masking property and an improved appearance. Suitable materials may be: ethyl cellulose, cellulose (KLUCEL®, Hercules C ( Drp.), (iv) ketomethyl (10) (10), _c:hemieal _.), polyethylidene ketone. The heart contains rifaximin-resistant gastric microparticle tablets can be based on the knowledge known to the skilled person Know the program choice - or a variety of cellulose and its contents: such as 2-based cellulose, methyl cellulose, propyl methyl cellulose as a poly-dioxide film coating. The alternative to cellulose ether is Certain acrylic resins such as methacrylic acid vinegar and nail Acrylic styrene copolymer. The polymer can be used in aqueous or organic solvent based systems. Incorporating flexibility to improve the coating film; by adding a plasticizer, the film risk can be reduced' and the film can be modified Adhesive. Typical examples of typical plasticizers include glycerin, propylene glycol, polyethylene glycol, triethyl glycerol, ethyl glycerol, glyceryl citrate, and citrate. Colorants are commonly used to improve = appearance. Water-soluble and/or organic solvent-soluble dyes, ^ albumin lake, titanium dioxide, iron oxide can be used. Finally, J adds a stabilizer such as EDTA to the coating. The rifaximin-resistant microparticles compressed into tablets were shown in the electron micrographs and the data in Figure 2 showed that compression did not change the integrity of the gastric-resistant microparticle layer of the compressed tablet. 312XP/Invention Manual ( Supplement) /%-10/96127712 22 200904415 In: Ϊ胶所: 利 rifaximin on the stomach microparticles by adding filler and free, sac inert diluent and slip agent with respect to particle size The advantageous nature of the instance package capability. The typical diluent of methylcellulose: Wang two-dimensional ^ micro μ r palace powder, lactose, kaolin, mannitol, nitrogen 'ethyl dry starch, which is between about 1 to about 225 mg of the door 't case' The rifaximin content in the gastric microparticles is based on the density of the gastric microparticles between the pens and the sputum. The density of the gastric microparticles is allowed to be applied to the habit:: 〇〇〇 嚢 140 140 140 140 140 140 140 Fuximin. All pharmaceutical preparations, namely hot-melt bags, lozenges and capsules, are used to treat inflammatory bowel diseases including Crohn's disease. The study on the bioavailability of the past is cross-cross (cross-嘹 = on the mother's beagle. The animals were treated with the (10) mg/day dose in the capsule prepared from the granules via the σ service route, and after at least 7 days of drug exclusion time (wash_〇ut peri〇d), Capsule Ten of 100 «g/day rifaximin treats it. 2, 4, 6, 8 and 24 hours before each administration and after each administration

A blood sample is collected from the jugular vein of the animal, and the sample is transferred to a tube containing heparin' and the plasma is separated by centrifugation. B Determination of rifaximin in plasma using an effective LC-MS/MS method and calculation of the maximum observed plasma concentration (Craax), time to Cmax (Traax), and area under the concentration-time curve (Auc) . The following examples are intended to be further illustrative of the objects of the invention and are intended to be limiting. 312XP/Invention Manual (Supplement y96-〗 0/96127712 23 200904415 [Example 1] (Preparation of rifaximin in gastric-resistant microparticles) 25,000 g of rifaximin powder and 125 g were used as a fluidizer Aerosil is filled in a Glab1:er system with a millimeter spray-jet fluid bed unit GlattGPC3®. Also used is 48 〇 7 grams of demineralized water '9281 grams of thiol acrylic acid sold under the registered trademark KOLLICOAT® MAE 100 p Ethyl acrylate copolymer, 1392 g of propylene glycol, 2475 g of talc, 557 g of titanium dioxide FU and 62 g of iron oxide E 172 were prepared in a mixer under stirring. The solid content of the suspension was made using a high speed homogenizer (Ultra Turrax). The mixture is uniformly mixed in the demineralized water. The prepared suspension is supplied to the spray system of the fluid bed device, and is sprayed through a 1·8 mm nozzle under a pressure of between 1.0 and 1.9 bar. The mixture of rifaximin powder and Aerosil 200 kept in a fluid bed by warm air flow. The conditions used are shown in Table i: [Table 1] Process parameters Preheating period Application coating solution drying Air flow in the mouth (m3/hour) 400±100 550±100 350150 Air temperature in the inlet () 60±2 60°C +10 50 + 2 Product temperature (°c) 32 25-27 30 + 2 Injection pressure ( Bar) (initial period) 1-1.5±0.1 Jet velocity (g/min) 150-200 Using the Malvern Mastersizer 2000 device, the obtained microparticles were subjected to particle size measurement analysis by light scattering technique, and the following results were obtained: 100% < 200 micron 99· 17% < 15 inch micron 312XP / invention specification (supplement) / 96-10 / 96127712 200904415 9〇. 03% < loo micron 48 · 37% < 50 micron 6. 20% < 1 〇Micron is 61.4% of the rifaximin phase in the total particle weight of the moon-resistant microparticle preparation. [Example 2] (S Ε Μ microscopic analysis of gastric resistant microparticles of rifaximin) Using SEM Philips The instrument was observed with 515. The gold was used to make rifaxixi gold with a current of 30 amps, and a gold layer of about 100 nm was used. The application of microparticles was reduced. (10) The camera recorded the image digitally. The image of the microparticles of =, Ming is shown in Fig. 1A, and at the same time, in Fig. [Example 3] (Stomach-resistant microparticles of rifaximin prepared in a hot-melt bag) 9.12 kg of the microparticles prepared according to Example j, (four) kilograms of sorbitol ==曰月(10) kilograms of aspartame artate), 0.21 kilograms of anhydrous citric acid, gum: 2.10 kilograms of mannitol, ... pounds of new orange peel money ΓΓ 2 2 cherry spice and 〇. 〇 7 kg of Qing in the G 5 mm mesh = upper sieved' then mixed in a V-blender for 2 minutes. The resulting material was dispensed into a blister bag containing 5 grams of product (equivalent to _mg rifaximin). The composition of the medicinal hot-melt bag is described in Table 2 below: [Table 2] 312XP/Invention Manual (supplement)/96_ 1 ο/% 127712 25 200904415 Ingredients _____ Quantity one (mg) Stomach-resistant rifaximin Microparticles (equivalent to 8 mg of rifaximin) 1303 26 Aspartame 70 Anhydrous Citric Acid 30 _0^6〇_ Pectin 300 6. 〇X- Mannitol 300 New Orange Peel DC 30 Yam The alcohol is exemplified by the implementation of the medicinal microparticles of rifaximin in the compressed tablet. The gastric-resistant rifaximin microparticles prepared in Example i, 593 g of sodium starch glycolate, and 1 g of magnesium stearate were sieved on a sieve having a mesh of 0.5 mm, and then mixed in a v-type mixer. 20 minutes. The resulting mixture was compressed to a final of 718 grams (equivalent to a rifaximin content of 400 mg) using an elliptical, scored 19 χ 9 mm punch; ingot machine (Fette 1200). , ''; The composition of the key agent is described in Table 3. [table 3 ]

Rifaximin-resistant gastric microparticles (phase 400 mg rifaximin) carboxymethyl-based fiber i steel ~ Avicel PH IQ] stearic acid town ~ ' ~~___ (mg) at 65 (K00 %__ 9〇Τ?Γ~ 34. 95 4. 8 7 24.31 ~m 718. 00

Lack of 铋/* 宙羽上-~——LLi〇· υυ 100. QQ Then use “vitamin film” to improve the appearance and taste-masking properties. I yuan; 312XP/invention manual (supplement)/96- 10/96127712 26 200904415 The contents are described in Table 4: [Table 4] Coating composition amount (mg) HPMC 14. 07 Di-titanium oxide 4. 10 Na-EDTA 0. 05 Propylene glycol 1. 37 Red gasified iron E 1 7 2 __ 0.41 [Example 5] ((Stomach-resistant microparticles of rifaximin prepared in hard capsules) 9.0 kg of gastric-resistant rifaximin microparticles prepared according to Example 与 and 110 Kg's talc and 1.1 kg of lactose are blended and sieved on a 5 mm. Use a conventional device like Zanasi LZ64 to mix the resulting j to a final weight of 46. 00 mg (equivalent to about 27 mg) The rifaximin content is introduced into the hard gelatin capsule type 000. The capsule composition is described in Table 5 ° 5] Capsule composition amount mg % rifaximin resistant stomach granules (equivalent to 270 mg rifaximin) , 406.00 88. 01 Talc 5. 00 ^IToi Lactose 50. 00 10. 8 Example 6 ] [Table [Real (Rifampicin Pharmaceutical Preparation) Solubility of Microparticles) According to American Music (USP), 283th edition, page 247, the stomach resistance of pharmaceutical preparations was evaluated. The evaluations were carried out in Examples 3, 3 and 4 by using the following conditions. 312XP/Invention Manual (Supplement)/96-10/96127712 27 200904415 The rifampicin-resistant gastric microparticles, and the rifaximin-resistant gastric microparticles containing rifaximin-resistant gastric microparticles Dissolution test of a hot melt bag and a pharmaceutical preparation containing a flavonoid-resistant gastric microparticle tablet: Equipment: SOTAX AT7 Smart

Medium: HC1 0. 1 N, PH 1 ; After 2 hours, a buffer containing 2% laurel "sodium citrate" was added, and the pH was raised to 6.8. Stirring speed: 100 rpm Temperature: 37 ° C Sampling time: 120, 135, 150, and 180 minutes. The content of dissolved rifaximin was measured by HPLC method. The results described in Table 6 are the average of six measurements and are expressed as relative to the total amount of rifaximin. Percent of dissolution. [Table 6] Medium and pH time solution (%) (minutes) Microparticle 1 bond bag HC1 0. 1 N, pH 1 120 2.41 1. 07 2. 57 sulphate buffer, pH 6.8 135 93. 8 67. 9 90. 3 Phosphate buffer, pH 6. 8 150 95. 4 81. 6 95. 1 phosphate buffer, pH 6. 8 165 97. 2 88. 1 96. 4 sulphate Buffer, pH 6.8 180 97. 4 93. 1 96. 2 After storage at 25 ° C for 12 months, the microparticles prepared as in Example 1 exhibited a similar dissolution profile, specifically 〇. 1%。 [1] The solution was dissolved in the phosphate solution at pH 1 for 120 minutes, and then dissolved in phosphate buffer solution at pH 6. 8 for 60 minutes after dissolution of 91.1%. [Example 7] (administered via oral route) Rifaximin beta in dogs Bioavailability) 312ΧΡ/Invention Manual (supplement)/96-10/96127712 28 200904415 According to the following procedure, we will treat four purebred female beagles weighing between 5.0 and 7 5 kg.吏 Each of the dogs was orally administered 100 « g / kg of rifaximin polymorph 0 prepared as gastric-resistant microparticles in gelatin capsules, and at least 7 days of drug exclusion time. 100 mg/kg of rifaximin polymorphism in gelatin capsules, before and after each dose, 1, 2, 3, 4, 6, 8, and 24 after administration: ::! The jugular vein of each animal belonging to each group collected a sample consisting of 2 ml of blood. 2 The sample was transferred to a heparinized tube and the H gray was divided into 500 μl aliquots and frozen at _2 〇t: Use the effective IX-MS/MS method to characterize plasma phlegm and according to the standard non-separated 3 J^ 9 following parameters: Calculated by non compartmental analysis n: "The maximum blood volume of rifaximin observed" Concentration; Ι-ax = time reached; rt is calculated by the linear trapezoidal rule under the concentration-time curve In the results in Table 7 clearly shows that rifaximin to pass on much shaped particles governance _ H I Preparation bioavailability. 7 phase is superior to other formulations [Table 7] for the preparation of gastric microparticles

Pharmacological parameters of lyfoxantine β compared to rifaximin P 312 ΧΡ / invention specification (supplement) / 96· 10/96127712 29 200904415 Preparation ^ rifaximin β is a _ microparticle of Liming

C m a X (ng/ml) T»ax (h) AUC〇~tlast AUCo-inf 2. 07 5 NC NC 32. 31 1.5 53 NC

[Example 8] (The bioavailability of rifaximin δ in the oral administration via the oral route) The purebred mothers having a weight between 5.0 and 7.5 kg were treated according to the following procedure. Beagle. Γ g = rifaximin polymorph δ prepared as a gastric-resistant microparticle in a gelatin capsule per oral administration of 1 mg/kg per dog, with a drug exclusion time of at least 7 days. The same animals received 1 mg/kg of rifaximin polymorph δ in gelatin. f A sample consisting of 2 ml of blood was collected from the jugular vein of each of the animals 2, 3, 4, 6, 8, and each of the groups before and after the administration. 2 The sample was transferred to a heparinized tube and centrifuged; the blood was condensed into 500 aliquots and frozen under _2 〇〇c. The knife uses an effective LC-MS/MS method to determine the evidence contained in the blood pool, and according to the standard non-compartment 曰 丨 f 丨 丨 刀 异 异 以下 以下 : : : : : : : : : : : 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大 最大Π Through the line (4) material, calculated under the concentration-time curve 312XP / invention manual (supplement) / 96-1 〇 /96127712 30 200904415 The morphological body of the Ming makes the living body prepared by the monthly microparticles use sputum. How to compare with other formulas [Table 8] ::::::: Granules prepared from rifaxi _ compared to rifaximin δ

801 830 1227 308. 31 V 11 eve 2 567. 56 ---- ί 2 1326 rifampicin ^ 1. _ sound & granules of granules g [Example 9] (treatment of Crohn's disease) == rifaximin resistant to f-resistant microparticles as described in Example 3: "Clinical multi-heart randomized trials relative to placebo in patients infected with Crohn's disease. 55 severely affected, Mild to moderate, period 'clon's disease patient with a CMI (Clone's Disease Activity Index; CnDhn Disease Active Bu (4) value between 2〇〇 and 3〇〇. Defined as low at the end of the study The percentage of patients with clinical remission of CDAI at 5 呈现 showed the primary endpoint. Patients who were randomized into two groups according to the following treatment schedule (Group A: 27 patients, and Group B: 28 patients) Treatment for 12 weeks: Group A: rifaximin 8 mg, administered twice daily for a total dose equal to 1600 g/day; Group B: placebo 'administered twice daily, this amount corresponds to activity Dosage content of ingredients. 312XP/Invention Manual (supplement)/96-10/96127712 31 200904415 Master of clinical remission after 12 weeks of treatment The endpoint was achieved by η 9% of patients treated with a gastric-resistant formula and 32 patients treated with a difficult placebo. In addition, only the patients in the group receiving rifaximin had failed treatment. Patients who were forced to leave clinical trials early discontinued treatment. The results are summarized in Table 9. Nine patients received placebo treatment [Table 9] Group [Example 10] A (rifaximin) 27 patients B (placebo) 2 8 patients

(32.1%) Number of fish treatment failures (3.4%) (Treatment characterized by protein patients) Reactivity values exceeded normal Crohn's disease At the beginning of treatment, 31 patients had exceeded the value (inflammation index in the process) ). For example, the protein C of Lu/Hang is divided into two groups: -纟 and 16-bit, 所述, as described in Example 3, the patient is treated with placebo. The main endpoint was in the group receiving rifaximin and the remaining patients and only (iv) in the group receiving rifaximin. In addition, the study was conducted, but the results of the treatment of the placebo group treated with the placebo were shown in Table 10. , 'There are 6 patients.咖魏明书(补件)/96,10/961在200904415 [表ίο] The number of clinical remissions with protein C values exceeding the normal value _ group of 16 patients receiving rifaximin treatment 10 (62.53⁄4) 5 patients received placebo treatment 3 (20%) 〉 Number of treatment failures 0 (0%) (403⁄4) One...叼曰% with excellent compatibility with Wan Yulian, Beibei and long-term use. BRIEF DESCRIPTION OF THE DRAWINGS Conditions are shown in Figure 1A: Scanning electron micrograph of rifaximin-resistant gastric microparticles, as described in Example 2 using SEM Philips 515 instrument: Experimental Figure 1B: rifaximin Scanning electron micrographs of single particles of gastric resistant microparticles, Lishaw SEM Philips 515 instrument, were obtained under the experimental conditions described in the examples. Figure 2: Dissolution distribution of gastric-resistant rifaximin in pharmaceutical preparations of microparticles, tablets and sachets, obtained by dissolving the apparatus s〇TAX AT 7 s. The test conditions are described in Example 6. Figure 3: Scanning micrograph of rifaximin-resistant gastric microparticles compressed into tablets was made using the SEM Philips 515 instrument and the experimental conditions of Example 2 = Lü Jishu. 312ΧΡ/Invention Manual (supplement)/9卜1〇/96127712 33

Claims (1)

200904415 X. Patent application scope: 1. A composition of w medicine containing antibiotics which can improve the utilization rate of the living body. 2. For the pharmaceutical composition of claim 1 of the patent scope, the improved bioavailability of antibiotics is attributed to gastric resistant microparticles. 3. The pharmaceutical composition of claim 2, wherein the antibiotic contained in the composition is rifaximin. 4: The pharmaceutical composition of claim 3, wherein the gastric resistance comprises the microscopic form comprising one or more polymorphic forms of rifaximin. A pharmaceutical composition according to claim 3, wherein the rifaximin polymorph form is selected from the group consisting of α, β, γ, 3, or ε. The pharmaceutical composition of claim 1, wherein the gastric-resistant rifaximin microparticles have a diameter of from about 微米 to about 9 Å. 7. The pharmaceutical composition of claim 2, wherein the gastric resistant rifaximin microparticles have a diameter of between about 10 microns and about 500 microns. 0之间。 7. The ratio of the pH of the drug is between 0.5 and 4. G and the pH is between 5.0 and 7. 7 Obtained from a soluble polymer. For example, the pharmaceutical composition of claim 4, wherein the polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl cellulose acetate, polyvinyl acetate and methacrylic acid. 312XP/Inventive Manual (Supplement)/96-1 〇/96127712 34 200904415 1 医药. The pharmaceutical composition of claim 4 or 5, wherein the amount of the gastric resistant polymer relative to the total amount of the microparticles The system is between 5% by weight and 75% by weight. ~ 11. The pharmaceutical composition according to any one of claims 4 to 6, wherein the 3H aging monthly mixture also contains a diluent, a plasticizer, an anti-agglomerating agent, an anti-adhesive agent, a slip agent, and a defoaming agent. Agent and coloring matter. 12. A pharmaceutical composition comprising: gastric-resistant rifaximin microparticles in a hot-melt bag between about 至 and about 3 〇〇〇 milligrams; between 〇 and about 45 〇 milligrams a sweetener selected from the group consisting of aspartame, sugar, xylitol, lactitol, SPLENDA8, sodium cyclamate, dextrose, fructose, glucose, lactose, And sucrose, or neo-hesperidin team: - or more; between about 50 mg of organic acid selected from the group consisting of citric acid, acetic acid, adipic acid, citric acid, and anti-butyl One or more of adipic acid, glutaric acid, malic acid, succinic acid (tetra), or tartaric acid; a suspending agent between about i and about 5 mils, selected from polyvinylpyrrolidone, One or more of sodium carboxymethylcellulose, pectin, sinosaur, or agar; mannitol ranging from 〇 to about 500 mg; sugar alcohol ranging from 〇 to about 4 〇〇〇 , which is selected from the group consisting of sugar alcohols such as lactitol, maltitol, mannitol, sorbitol, and xylitol, triterpene, dextrin, or maltodextrin - or a plurality of fragrances ranging from about 300 to about 300 mg, beans selected from the group consisting of fruit or botanical flavors; and a slipping agent ranging from about _ to 毫, which is selected from the group consisting of silicones, magnesium stearate, Or one or more of the talc days. 13. A pharmaceutical composition comprising: 312XP/invention specification (supplement)/96·10/96127712 35 200904415 a gastric-resistant rifampicin between about 50 and about 1000 mg in a compressed tablet a microparticle; between about i and about 500 mg, selected from the group consisting of dicalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose (Avicel®), hydroxypropyl methylcellulose, corn starch, One or more of lactose, kaolin, mannitol, sodium chloride, dry powder; between about 1 and about 5 (10) milligrams of binder selected from starch, gelatin, sugars such as sucrose, glucose, right-handed One or more of sugar, lactose, synthetic gum, sodium sea oxalate, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, ethyl cellulose, water, wax, alcohol a lubricant between about 〇 and about 2 〇, selected from one or more of talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol; a slip agent of about 2 〇 milligrams, selected from one or more of colloidal cerium oxide and talc; To about 200 mg of disintegrant between Qi! , selected from the group consisting of methylcellulose nano, corn and potato powder, croscarmellose, crospovidone, sodium starch glycolate + one or more; a coloring agent between 0 and about 10 mg, selected from one or more of titanium dioxide and iron oxide; a sweetener between about 〇 and about 500 mg, selected from the group consisting of sucrose, sorbitol, and mannitol One or more of saccharin, acesulfame, and new cellulite. 14. A film coating composition for a tablet comprising: a polymer between about 0 and about 5 milligrams selected from the group consisting of cellulose and its substitutes (tetra)propylcellulose, W-based cellulose, Propyl-mercapto cellulose 'specific acrylic resin, such as mm such as methyl acrylate and thiol propylene j 曱 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨First, between about 〇 to about 5 mg, 312 ΧΡ / invention specification (supplement) / 96-10/96127712 36 200904415 plasticizer selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, triethylene glycol glycerol, B One or more of a thiolated monoglyceride, a citrate, and a phthalate; a stabilizer between about 〇 and about 1 mg, such as EDTA; a color between about 〇 and about ίο耄An agent selected from one or more of albumin lake (alb(10)h lake), titanium dioxide, iron oxide. 15. A pharmaceutical composition comprising: r a gastric-resistant coufoximin microparticle of between about 50 and about 450 mg in a hard gelatin capsule; a lubricant between about 〇 and about 25 mg, selected from the group consisting of talc, magnesium stearate, One or more of stearic acid dance, stearic acid, hydrogenated vegetable oil, polyethyl alcohol; a diluent between about i and about 225 gram, selected from the group consisting of phosphoric acid, sulfuric acid, cellulose, micro One or more of crystalline cellulose, propyl decyl cellulose, corn house powder, lactose, high collapse soil, mannitol, sodium vaporized, dried starch. , 'J6. Use of a gastric-resistant microparticle containing rifaximin for the manufacture of a pharmaceutical preparation for inflammatory bowel disease for / oral therapy. Use of the 16th item of the wide range: wherein the inflammatory bowel disease is Crohn's disease. 2. The use of the fourth item of the fourth paragraph, in which the value of the C-reactive protein of the diseased patient is higher than the standard. 19. A method for producing rifaximin containing a size of a stomach-like microparticle having a size of about 9 Å micrometers consisting of the following steps: containing gastric resistance: a method of releasing a release agent, an anti-adhesive agent, Anti-agglomerating agent, sliding material, 'plasticizer dilute aqueous suspension at pressure between 1Q // bag and coloring matter, * 5 bar and flow rate between 15 〇 and 312XP / invention manual (supplement) / 96· 1 〇/96127712 37 200904415 300 g / min sprayed through a nozzle into a fluid bed device, heated in the fluid bed device at a temperature between 50 ° C and 75 ° C and 450 to 650 cubic meters The air flow output in meters per hour keeps the active ingredient rifaximin mixed with the fluidity enhancer in suspension. 20. Use of a pharmaceutical composition according to item 3 of the patent application, which has a high utilization rate of rifaximin. 312XP/Invention Manual (supplement)/96-10/96127712 38 200904415 VII. Designated representative map: (1) The representative representative of the case is: (1A). (2) A brief description of the symbol of the representative figure: Benefit C 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 312XP/Invention Manual (supplement)/96-10/96127712 5 200904415 Name: (Chinese/English) Alpha Weissman Company / ALFA WASSERMANN SpA Representative: (Chinese / English) Prostitute Paggio Giorgio / Giampaolo Girotti Residence or establishment Address: (Chinese / English) Yida Via Enrico Fermi, 65020 Alanno (PE), Italy Nationality: (Chinese / English) Italian / Italian III. Inventor: (Total 4 persons) Name: (Chinese) /English) (1) Giuseppe Claudio Viscomi (2) Ernesto Palazzini / Ernesto Palazzini (3) Virgin Saboni / Villiam Zamboni (4) Maria Rosario Pantaleo Nationality (Chinese / English) (1) ~ (4) Italy / Italian 312XP / invention manual (supplement) / 96-10/96127712 1